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Estrogen plays an important role in initiating and promoting breast cancer (reviewed in [1]).
This pathway shows the rate-limiting biosynthesis of estrogen from androgens by aromatase and its
inhibition by aromatase inhibitors/inactivators in postmenopausal women. Aromatase, an enzyme of the
cytochrome P450 (CYP450) subfamily and the product of the CYP19A1 gene, is highly expressed in the
placenta and in the granulose cells of ovarian follicles in premenopausal women [2]. Its expression
depends on cyclical gonadotropin stimulation [3]. In addition, aromatase is also present at lower
levels in several nonglandular tissues that include subcutaneous fat, liver, muscle, brain, normal
breast and breast cancer tissue [4]. Estrogen production after menopause is solely from nonglandular
sources, particularly subcutaneous fat. In menopause, androstenedione produced in the adrenals and,
to a small extent, testosterone produced in the ovaries are released to the circulation and then
sequestered to nonglandular tissues (e.g., liver and breast cells), where they are converted to
estrone and estradiol, respectively, by aromatase located in these tissues [5]. In the liver and
in breast tissue, estrone and estradiol undergo oxidation by CYP450s to a number of hydroxylated
metabolites [6]. Estrone and estradiol in these tissues also undergo conjugation by sulfotransferases
(SULTs) or deconjugation by steroid sulfatase (STS) [7]. In all tissues, hydroxysteroid (17-beta)
dehydrogenase (HSD17B) converts androstenedione to testosterone and estrone to estradiol [5].
Drugs that effectively inhibit the aromatase-mediated synthesis of estrogens in peripheral tissues
including the breast, thus depriving the system of estrogens, are widely used in the treatment of
breast cancer [4]. These drugs include the nonsteroidal triazole derivatives anastrozole and letrozole
and the steroidal exemestane.
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| Zeruesenay Desta, Anne Nguyen, David Flockhart,
Todd Skaar, Rebecca Fletcher, Richard Weinshilboum, Dorit S. Berlin, Teri E. Klein, Russ B. Altman
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Pharmacogenet Genomics. 2009 Jul;19(7):554-555. PMID: 19512956
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| October 15, 2007 |
| November 12, 2009 |
- Russo J, Russo IH: The role of estrogen in the initiation of breast cancer. J Steroid
Biochem Mol Biol 2006; 102:89-96.
- Labrie F, Simard J, Luu-The V, Pelletier G, Belghmi K, Belanger A: Structure, regulation and role
of 3 beta-hydroxysteroid dehydrogenase, 17 beta-hydroxysteroid dehydrogenase and aromatase
enzymes in the formation of sex steroids in classical and peripheral intracrine tissues. Baillieres
Clin Endocrinol Metab 1994; 8:451-474.
- Palermo R: Differential actions of FSH and LH during folliculogenesis. Reprod Biomed Online 2007;
15:326-337.
- Rieber AG, Theriault RL: Aromatase inhibitors in postmenopausal breast cancer patients.
J Natl Compr Canc Netw 2005; 3:309-314.
- Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin SX, Pelletier G: Endocrine and
intracrine sources of androgens in women: inhibition of breast cancer and other roles of
androgens and their precursor dehydroepiandrosterone. Endocr Rev 2003; 24:152-182.
- Jefcoate CR, Liehr JG, Santen RJ, Sutter TR, Yager JD, Yue W, Santner SJ, Tekmal R, Demers L,
Pauley R, et al: Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl
Cancer Inst Monogr 2000:95-112.
- Raftogianis R, Creveling C, Weinshilboum R, Weisz J: Estrogen metabolism by conjugation.
J Natl Cancer Inst Monogr 2000:113-124.
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